Alkynylation of cotarnine hydrochloride by Ag(I) acetylenides

Article abstract of DOI:10.1023/B:CONC.0000011125.72785.fe

1-Organoacetylene derivatives were prepared by reaction of cotarnine hydrochloride with silver organoacetylenides with brief heating in acetonitrile. The structure of one of these, 1-(3 -hydroxypropyn-1-yl)-2-methyl-6,7- methylenedioxy-8-methoxy-1,2,3,4-t

Full text of DOI:10.1023/B:CONC.0000011125.72785.fe

Chemistry of Natural Compounds, Vol. 39, No. 5, 2003
ALKYNYLATION OF COTARNINE HYDROCHLORIDE
BY Ag(I) ACETYLENIDES
L. Yu. Ukhin,1 K. Yu. Suponitskii,2 and V. G. Kartsev3
UDC 547.833.6+547.314
1-Organoacetylene derivatives were prepared by reaction of cotarnine hydrochloride with silver
′
organoacetylenides with brief heating in acetonitrile. The structure of one of these, 1-(3 -hydroxypropyn-1-
yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline, was proved by an X-ray structure
analysis.
Key words:
cotarnine hydrochloride, silver organoacetylenides, alkynylation, X-ray structure analysis.
Organoacetylenides of Cu(I) and Ag(I) are extensively used in organic synthesis [1, 2] because of their peculiarities
that are not typical of analogous compounds of active metals, i.e., their hydrolytic stability and the ability to use them in the
presence of most functional groups. In addition to the reaction with covalent halides, the most famous of which is the
Castro—Sladkov reaction [3, 4], these compounds are used for alkynylation of organic cations. Acylpyridinium and
acylquinolinium salts react with silver phenylacetylenide to form α-phenylethynyl derivatives of N-acyl-1,2-dihydropyridines
and N-acyl-1,2-dihydroquinolines [5]. Reaction of diazonium salts with silver organoacetylenides produces azoethynyl
compounds [6-9]. 1-Aminobenzimidazolium salts are alkynylated byCu(I) and Ag(I) phenylacetylenides at the 2-position with
subsequent cyclization and rearrangement into pyrazole derivatives [10]. Iminium salts react smoothly with Cu(I) and Ag(I)
phenylacetylenides to form the corresponding propargylamines [11]. Analogous behavior can be expected from cotarnine
hydrochloride, which possesses a wide spectrum of biological activity and has the structure of a cyclic iminium salt. Such
modification of cotarnine promises to produce new physiologically active compounds.
O
O
∆
−
H C
2
H C
2
+
AgCl
AgC CR
Cl
CH
+
+
N
N
O
O
CH CN
3
CH
3
3
2
H
CR
H CO
3
H CO
3
1
3
CH O
3
CH O
COOC H
2
2
5
CH
CH
3
HO
CH O
CHO
CH O
F
R =
2
2
CH OH
2
OH
N
CH
3
3
a
d
e
b
c
f
CH
3
Br
C H O
2
5
CH CH OH
CH O
CH O
CHO
2
2
2
2
CH O
O
O
2
j
g
i
k
h
CH
3
Cl
CH O
H NCO
2
CH O
NO
Cl
CH O
CH O
2
2
2
2
2
CH O
O
O
2
p
m
n
o
l
1) Scientific-Research Institute of Physical and Organic Chemistry, Rostov State University, 344090, Rostov-on-Don,
pr. Stachki, 194/2, fax (8632) 43 46 67, e-mail: may@ipoc.rsu.ru; 2) A. N. Nesmeyanov Institute of Elementorganic
Compounds, Russian Academy of Sciences, 117813, Moscow, ul. Vavilova, 28, e-mail: kira@xrlab.ineos.ac.ru; 3) OOO
"Interbioscreen," 142432, Chernogolovka, MoscowDistrict, Institutskii pr., 8, fax (095) 788 06 52, e-mail: screen@nsp.chg.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 395-400, September-October, 2003. Original article submitted
September 5, 2003.
0009-3130/03/3905-0482$25.00 ©2003 Plenum Publishing Corporation
482

TABLE 1. PMR Spectra of 3
Compounds
Solvent, , ppm, J/Hz
3a
3b
3c
(CDCl3): 1.1-1.9 (11H, m, CH2, OH), 2.48 (3H, s, NCH3), 2.60 (2H, m, 2H-4), 2.85 (2H, m, 2H-3), 3.98 (3H, s, OCH3),
4.73 (1H, s, H-1), 5.86 (2H, s ( split), OCH2O), 6.28 (1H, s, H-5)
(CDCl3): 2.41 (3H, s, NCH3), 2.5-3.0 (4H, m, 2H-3+2H-4), 3.92 (3H, s, OCH3), 4.66 (2H, d, J = 1.8, CH2O), 4.69 (1H,
s, H-1), 5.86 (2H, s, OCH2O), 6.28 (1H, s, H-5), 6.90 (4H, m, Ar-H)
(CDCl3): 1.39 (3H, t, J = 7.1, CH3), 2.41 (3H, s, NCH3), 2.55 (2H, m, 2H-4), 2.73 (3H, s, CH3), 2.85 (2H, m, 2H-3),
3.65 (3H, s, CH3), 3.90 (3H, s, OCH3), 4.33 (2H, q, J = 7.1, CH2), 4.71 (1H, s, H-1), 4.76 (2H, d, J = 1.5, CH2O), 5.84
(2H, s, OCH2O), 6.25 (1H, s, H-5), 6.87 (1H, dd, 3J = 8.8, 4J = 2.5, H-6 ), 7.14 (1H, d, J = 8.8, H-7 ), 7.66 (1H, d,
J = 2.5, H-4 )
3d
3e
3f
(DMSO-d6): 2.38 (3H, s, NCH3), 2.54 (2H, m, 2H-4), 2.77 (2H, m, 2H-3), 3.96 (3H, s, OCH3), 4.03 (2H, dd, J = 6.0,
J = 1.7, CH2O), 4.52 (1H, s, H-1), 4.87 (1H, t, J = 6.0, OH), 5.89 (2H, s, OCH2O), 6.29 (1H, s, H-5)
(CDCl3): 1.48 (6H, s, 2CH3), 2.48 (3H, s, NCH3), 2.60 (2H, m, 2H-3), 3.85 (2H, s ( ), 2H-3), 3.99 (3H, s, OCH3), 4.71
(1H, s, H-1), 5.87 (2H, m, OCH2O), 6.30 (1H, s, H-5)
(DMSO+CCl4): 2.84 (3H, s, NCH3), 3.20-3.45 (4H, m, 2H-3+2H-4), 3.84 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.89 (2H,
s, CH2O), 5.39 (1H, s, H-1), 5.97 (2H, s, OCH2O), 6.42 (1H, s, H-5), 7.17 (1H, d, J = 8.0, H-6 ), 7.37 (1H, d, J = 1.7,
H-3 ), 7.47 (1H, dd, 3J = 8.0, 4J = 1.7, H-5 ), 9.81 (1H, s, CHO), 12.30 (1H, s, NH)
3g
3h
(CDCl3): 1.45 (3H, t, J = 7.0, CH3), 2.40 (3H, s, NCH3), 2.50-2.90 (4H, m, 2H-4+2H-3), 3.91 (3H, s, OCH3), 4.10 (2H,
q, J = 7.0, CH2), 4.68 (1H, s, H-1), 4.87 (2H, d, J = 1.5, CH2O), 5.85 (2H, s, OCH2O), 6.27 (1H, s, H-5), 7.13 (1H, d,
J = 8.0, H-6 ), 7.36 (2H, m, H-3 +H-5 ), 9.82 (1H, s, CHO)
(CDCl3): 2.37 (3H, s, NCH3), 2.40-2.60 (2H, m, 2H-4), 265-2.90 (2H, m, 2H-3), 3.88 (3H, s, OCH3), 4.67 (1H, s, H-1),
4.92 (2H, d, J = 1.7, CH2O), 5.82 (2H, m, OCH2O), 6.20 (1H, s, H-5), 7.38 (2H, m, Ar-H), 7.54 (1H, m, Ar-H), 7.90
(2H, m, Ar-H), 8.19 (1H, d, J = 8.5, Ar-H)
3i
3j
(CDCl3): 2.57 (3H, s, NCH3), 2.64 (2H, m, 2H-4), 2.94 (2H, m, 2H-3), 4.03 (3H, s, OCH3), 4.92 (1H, H-1), 5.87 (2H, s,
OCH2O), 6.32 (1H, s, H-5), 7.24 (3H, m, Ar-H), 7.39 (2H, m, Ar-H)
(DMSO-d6): 2.36 (2H, t, J = 6.4, CH2), 2.89 (3H, s, N+CH3), 2.80-3.50 (6H, m, 2H-4+2H-3+CH2), 4.02 (3H, s, OCH3),
4.65 (1H, m, OH), 5.26 (1H, s, H-1), 5.98 (2H, d, J = 2.4, OCH2O), 6.43 (1H, s, H-5), 12.14 (1H, s, N+H)
(CDCl3): 2.43 (3H, s, NCH3), 2.50-2.96 (4H, m, 2H-3+2H-4), 3.93 (3H, s, OCH3), 4.70 (1H, s, H-1), 4.96 (2H, d,
J = 1.7, CH2O), 5.85 (2H, s, OCH2O), 6.25 (1H, d, J = 8.5, H-3 ), 6.27 (1H, s, H-5), 6.86 (1H, dd, 3J = 8.5, 4J = 2.4,
H-6 ), 6.89 (1H, d, J = 2.4, H-8 ), 7.34 (1H, d, J = 8.5, H-4 ), 7.62 (1H, d, J = 8.5, H-5 )
3k
3l
3m
3n
(DMSO-d6): 2.38 (3H, s, CH3), 2.43 (3H, s, NCH3), 2.5-3.0 (4H, m, 2H-3+2H-4), 3.94 (3H, s, OCH3), 4.70 (1H, s,
H-1), 4.76 (2H, d, J = 1.7, CH2O), 5.85 (2H, s, OCH2O), 6.14 (1H, s, H-3 ), 6.26 (1H, s, H-5), 6.88 (1H, dd, 3J = 8.5,
4J = 2.4, H-6 ), 6.89 (1H, d, J = 2.4, H-8 ), 7.46 (1H, d, J = 8.4, H-5 )
(CDCl3): 2.41 (3H, s, NCH3), 2.5-3.0 (4H, m, 2H-3+2H-4), 3.92 (3H, s, OCH3), 4.68 (1H, s, H-1), 4.79 (2H, d, J = 1.8,
CH2O), 5.85 (2H, s (split ), OCH2O), 6.27 (1H, s, H-5), 7.00 (2H, d, J = 9.2, H-2 +H-6 ), 8.15 (2H, d, J = 9.2, H-3 +
H-5 )
(CDCl3): 2.65-3.65 (4H, m, 2H-3+2H-4), 2.88 (3H, s, NCH3), 3.98 (3H, s, OCH3), 4.79 (2H, d, J = 1.6, CH2O), 5.21
(1H, s, H-1), 5.88, 5.93 (2H, dd, J =1.2, OCH2O), 6.30 (1H, s, H-5), 6.86 (1H, d, J = 8.8, H-6 ), 7.13 (1H, dd, 3J = 8.8,
4J =2.4, H-5 ), 7.35 (1H, d, J = 2.4, H-3 ), 13.31 (1H, s, N+H)
3o
3p
(CDCl3): 2.44 (3H, s, NCH3), 2.5-3.0 (4H, m, 2H-3+2H-4), 3.93 (3H, s, OCH3), 4.70 (2H, d, J = 1.7, CH2O), 4.72 (1H,
s, H-1), 5.36 (2H, s, OCH2O), 6.28 (1H, s, H-5), 6.93 (3H, m, Ar-H), 7.24 (2H, m, Ar-H)
(DMSO-d6): 2.33 (3H, s, NCH3), 2.5-2.9 (4H, m, 2H-3+2H-4), 3.89 (3H, s, OCH3), 4.55 (1H, m, H-1), 4.92 (2H, d,
J = 1.5, CH2O), 5.89 (2H, d, J = 1.0, OCH2O), 6.27 (1H, s, H-5), 7.0-7.9 (6H, m, 4Ar-H+NH2)
In fact, it has been noted [12] that cotarnine hydrochloride (1) reacts readilywith silver organoacetylenides 2 (prepared
from the corresponding acetylenes 4) upon brief heating in CH CN to form acetylene derivatives 3.
3
The free bases of 3 cannot always be isolated as crystalline solids. As a rule, oils formed in such instances give
hydrochlorides that crystallize well (3f, h, j, n).
The structure of 3 was proved using PMR spectra (Table 1) and confirmed by an X-ray structure analysis of
1-(3′-hydroxypropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3d)(Tables2and3, Figs.
1 and 2).
483

TABLE 2. Bond Lengths (d) in 3d
Bond
d/
Bond
d/
O1-C4
O1-C5
O2-C6
O2-C5
O3-C14
O4-C3
O4-C15
N1-C1
N1-C10
N1-C11
C1-C12
1.382(7)
1.419(6)
1.405(7)
1.409(7)
1.412(6)
1.375(6)
1.401(7)
1.458(6)
1.461(7)
1.484(6)
1.487(8)
C1-C2
C2-C8
1.539(7)
1.378(7)
1.408(8)
1.377(8)
1.372(9)
1.337(9)
1.398(8)
1.485(7)
1.508(7)
1.163(8)
1.461(8)
C2-C3
C3-C4
C4-C6
C6-C7
C7-C8
C8-C9
C9-C10
C12-C13
C13-C14
0
b
c
3 d 1
O 3
C 1 4
C 1 5
C 1 3
O 4
C 1 2
O 2
C 3
C 1
3 d
′
C 4
O 3
′
C 2
N 1
′
C 1 1
N 1
C 5
3 d 1
′
O 3
C 6
C 8
C 1 0
3 d
O 2
a
C 7
C 9
Fig.1
Fig.2
Fig. 1. General view of 3d.
Fig. 2. Section of crystal packing of 3d. H-Bonded clusters formed by two molecules are shown.
The crystal of 3d contains two symmetrically independent molecules 3d and 3d′, the structures of which differ mainly
in the orientation of the CH OH group relative to the C(13)–C(14) bond. In 3d, the torsion angle C(12)–C(13)–C(14)–O(3)
2
is 1.1° whereas it is -140.9° in 3d′ (Fig. 1). The five-membered ring in both molecules has the envelope conformation [C(5)
and C(5′) deviate from the ring plane by 0.191 (3d) and 0.350 Å (3d′), respectively]. The isoquinoline fragment has the half-
chair conformation [atoms N(1) and C(10) deviate from the C(1)–C(2)–C(8)–C(9) plane by -0.538 and 0.233 Å, respectively,
in 3d and by -0.514 and -0.272 Å, respectively, in 3d′]. The methoxyl group is twisted by31.9 and 42.1° relative to the benzene
ring in 3d and 3d′, respectively.
The difference in the orientation of the hydroxyls is apparently caused by the formation of a system of H-bonds. The
bond O(3)–H(3)...N(1′) [O...N 2.747(8) Å, H...O 1.92 Å, OHN 164°] forms between 3d and 3d′; O(3′)–H(3′)...O(3) (-x+1, -y+1,
-z) [O...O 2.844(8) Å, H...O 2.01 Å, OHO 169°], between 3d′ and 3d1 (Fig. 2). Thus, the crystal is constructed of H-bonded
clusters formed by four molecules.
484

TABLE 3. Bond Angles ( ) in 3d
Angle
w/deg
Angle
w/deg
C4-O1-C5
C6-O2-C5
C3-O4-C15
C1-N1-C10
C1-N1-C11
C10-N1-C11
N1-C1-C12
N1-C1-C2
C12-C1-C2
C8-C2-C3
C8-C2-C1
C3-C2-C1
O4-C3-C4
O4-C3-C2
C4-C3-C2
C6-C4-C3
103.3(5)
105.0(6)
119.3(5)
112.0(5)
109.6(5)
112.5(5)
113.2(5)
106.9(5)
110.2(5)
120.0(6)
123.1(6)
116.8(6)
123.4(8)
117.2(7)
119.4(6)
116.9(7)
C6-C4-O1
C3-C4-O1
O2-C5-O1
C7-C6-C4
C7-C6-O2
C4-C6-O2
C6-C7-C8
C2-C8-C7
C2-C8-C9
C7-C8-C9
C8-C9-C10
N1-C10-C9
C13-C12-C1
C12-C13-C14
O3-C14-C13
111.9(6)
131.2(8)
110.1(6)
127.0(7)
125.2(8)
107.8(8)
115.6(6)
121.1(6)
119.4(6)
119.4(6)
114.6(5)
108.5(5)
174.8(7)
179.0(7)
114.1(5)
TABLE 4. Propargyl Ethers of Phenols 4: HC CCH2OR
Amount
Reaction
IR spectrum
Compound
Yield, %
mp, C
Liquid
phenol,
mole
acetone,
mL
-1
time, h
(mineral oil), , cm
4b
0.2
7.510e+17 44.573665 5.05366e+15
2120 (C C),\
3300 ( CH) (film)
4f
4h
4k
4l
0.1
0.1
100
75
4.5
7
53
65
49
62
64
64
55
92-93 (from CCl4—petrol.ether, 1:2 )
82 (from petrol.ether)
2114 (C C), 3240 ( CH)
2120 (C C), 3287 ( CH)
0.025
0.07
0.2
35
3
117-120 (from toluene—petrol.ether, 1:2 ) 2114 (C C), 3267 ( CH)
130-135 (from i-PrOH) 2127 (C C), 3300 ( CH)
115-117 (from toluene—petrol.ether, 1:1) 2127 (C C), 3260 ( CH)
75
6
4m
4n
4p
150
50
6
0.05
0.1
5
50 (from petrol.ether)
148-152 (from EtOH)
2114 (C C), 3267 ( CH)
2100 (C C), 3200 ( CH)
50
4
EXPERIMENTAL
IR spectra were recorded on a Specord IR-75 instrument in mineral oil. PMR spectra were recorded on a UNITY-300
(Varian) spectrometer. Analytical data of all compounds corresponded to those calculated.
Syntheses of Starting Compounds.
1. Syntheses of Propargyl Ethers of Phenols. Propargyl ethers 4(b,f,h,k,l,m,n,p) were synthesized by Claisen
condensation [13] by boiling equimolar amounts of phenol and K CO with a 10% excess of propargyl bromide in acetone for
2
3
3-7 h with TLC monitoring. The reaction mixture was filtered while hot. The precipitate was washed with hot acetone. The
filtrate was cooled. The propargyl ether was precipitated by water. The solid ethers were filtered off. The precipitate on the
filter was treated with hot water. The insoluble part was combined with the precipitated ether and recrystallized. The liquid
ether obtained from p-fluorophenol (b) was separated in a separatory funnel, washed with water, dried over Na SO , and
2
4
distilled at reduced pressure using a water aspirator. The fraction distilling at 114-118° at 20 mm Hg was collected.
485

Characteristic C C and C H stretching-vibration bands in the IR spectra showed the presence in the compounds of the
propargyl group. The final proofofstructure in all instances was the synthesis ofthe corresponding cotarnine derivatives. Table
4 summarizes the synthesis data and properties of these ethers.
Propargyl Ether of Dimecarbine (4c). Dimecarbine was alkynylated by a variation of the literature method [14].
A suspension of1,2-dimethyl-3-ethoxycarbonyl-5-hydroxyindole (1.5 g, 6.4 mmole) was treated with NaOH(0.52 g, 13 mmole)
in H O (1 mL) and propargyl bromide (0.6 mL, 8 mmole), boiled for 2 min, and cooled. A crystalline solid was precipitated
2
with water, filtered off, dried, and chromatographed over an Al O column using CHCl . The solvent was evaporated. The
2
3
3
solid was ground with CH OH, filtered off, and washed with cold CH OH to afford a colorless substance, mp 123-125°C. Yield
3
3
1.1 g (63%).
PMR spectrum (CDCl , , ppm, J/Hz): 1.43 (3H, t, J = 7.1, CH ), 2.50 (1H, t, J = 2.2, CH), 2.72 (3H, s, CH ), 3.64
3
3
3
3
4
(3H, s, NCH ), 4.36 (2H, q, J = 7.1, CH ), 4.74 (2H, d, J = 2.2, CH ), 6.90 (1H, dd, J = 8.8, J = 2.4, H-6), 7.16 (1H, d,
J = 8.8, H-7), 7.73 (1H, d, J = 2.4, H-4). IR spectrum ( , cm ): 2127 (C C), 3233 ( CH), 1694 (CO).
3
2
2
-1
Propargyl Ether of 4-Hydroxy-3-ethoxybenzaldehyde (4g). NaOH (0.8 g, 0.02 mole) was treated with DMSO
(5 mL), ground with a glass rod into a fine powder, treated with 4-hydroxy-3-ethoxybenzaldehyde (1.66 g, 0.01 mole), ground
with a glass rod for 10 min, treated with a toluene solution of propargyl bromide (1.35 mL, 0.01 mole, 80%), and left for
12 h. Water was added. The mixture was kept on ice for 2 h. The precipitate was filtered off and recrystallized from petroleum
-1
ether to afford colorless crystals (1.4 g, 68%), mp 75-77°C. IR spectrum ( , cm ): 2114 (C C), 3247, 3267 ( CH), 1687 (CO).
2. Method for Synthesizing Acetylenides (see also [15]). A solution of AgNO (1.7 g, 0.01 mole) in a mixture of
3
EtOH (10 mL) and conc. NH OH (10 mL) was added to a solution of an acetylene derivative (0.01 mole) in EtOH. Liquid
4
acetylene derivatives were dissolved in EtOH (10 mL); solid, in EtOH (40-50 mL), as a rule, with heating. The alcohol can be
replaced with acetone or dioxane if the solubilityin EtOH is poor (for example, 2o). The resulting white precipitate was filtered
*
off in a Buchner funnel; washed with EtOH, ether, and petroleum ether; and dried in the dark in air or a vacuum desiccator.
**
3. Method for Synthesizing Cotarnine Acetylene Derivatives (3). Cotarnine hydrochloride (1 g, 4 mmole) and
acetylenide (2, 5 mmole) in CH CN (10 mL) were stirred for 10 min at room temperature, refluxed for 5 min, and filtered while
3
hot. The precipitate on the filter was washed with hot CH CN.
3
1-Ethynylcyclohexan-1′-ol-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3a). The
filtrate was cooled with ice. The precipitate was filtered off, washed with cold CH CN, and dried. Colorless crystals, mp 135°C,
3
yield 0.66 g (49%).
1[(4′-Fluorophenoxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3b)
was prepared analogously. It was additionally purified by chromatography over an Al O column (CHCl ). The CHCl was
2
3
3
3
evaporated. The resulting oil was recrystallized by grinding with petroleum ether. Colorless compound, mp 100°C, yield
1.08 g (75%).
1-[(1″,2″-Dimethyl-3″-ethoxycarbonyl-5″-indolyloxy)propyn-1′-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-
1,2,3,4-tetrahydroisoquinoline (3c) was prepared analogously. The oil from the Al O column was ground with EtOH, from
2
3
which the resulting precipitate was recrystallized. Colorless compound, mp 175-180°C, yield 0.79 g (42%).
1-(3′-Hydroxypropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3d). Solvent
(CH CN) was evaporated. The oilyremainder was dissolved in CHCl and chromatographed over an Al O column, discarding
3
3
2 3
a small initial fraction. The CHCl was evaporated. The oil that solidified upon grinding was recrystallized from toluene.
3
Colorless crystals, mp 154-156°C, yield 0.47 g (44%).
______
*Some silver organoacetylenides can decompose on storage to form explosive products. According to our observations, such
unstable acetylenides include silver derivatives ofphenylethynylcarbinol and diphenylethynylcarbinol. Therefore, acetylenides
should be prepared immediately before the synthesis in quantities required for the reaction. Schott filters should not be used
(decomposition can occur upon scraping the dry acetylenide with a spatula). Remaining compounds should be destroyed by
decomposing them with acid after work is completed.
**Commercial acetylene derivatives were used to synthesize 3(a,d,e,i,j,o).
486

1-(3′-Hydroxy-3′-methyl)butyn-1-yl-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3e)
was prepared analogously to 3d without discarding the initial fraction. The oil that solidified upon grinding with petroleum
ether was recrystallized from hexane. Colorless crystals, mp 110°C, yield 0.68 g (57%).
1-[3′-(2″-Methoxy-4″-formylphenoxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline hydrochloride (3f) was prepared analogouslyto 3e. The oil from the column was dissolved in i-PrOH
(20 mL), treated with conc. HCl (0.4 mL), cooled with ice, and ground with a rod. The precipitate was filtered off, washed with
ether, and dried. Colorless crystals, mp 155°C (i-PrOH), yield 1 g (57%).
1-[3′-(2″-Ethoxy-4″-formylphenoxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline (3g) was prepared analogously to 3e. The oil from the column was ground with petroleum ether and
cooled with ice until solidified. The solid was filtered off, washed with petroleum ether, and dried in vacuum. Colorless
compound, mp 110-115°C (i-PrOH), yield 1.42 g (68%).
1-[3′-(α -Bromo-β-naphthoxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline hydrochloride (3h). The filtrate was cooled and filtered through a dense filter. The solvent was
evaporated. The oil was ground with acetone and conc. HCl (0.5 mL). The resulting solid was filtered off, washed with acetone,
and dried. Colorless crystals, mp 195-200°C (i-PrOH), yield 0.9 g (45%).
1-(2′-Phenylethynyl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3i). The CH CN
3
was evaporated. The oil was dissolved in CHCl and chromatographed over an Al O column. The solvent was evaporated.
3
2 3
The resulting oil crystallized after 1 d. The compound is verysoluble in most organic solvents and crystallizes poorly. mp 80°C
(aqueous CH OH), yield 1 g (79%).
3
1-(4′-Hydroxybutyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3j). The
CH CN was evaporated. The oil was dissolved in acetone (10 mL) and treated with conc. HCl (1 mL) in acetone (3 mL). The
3
resulting precipitate was filtered off and recrystallized from CH CN. Colorless compound, mp 225-230°C (dec.), yield
3
0.58 g (46%).
1-[3′-(7″-Coumaroxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3k).
An oil precipitated from the filtrate and crystallized upon grinding with CH OH. Colorless crystals, mp 143-145°C (CH OH),
3
3
yield 0.68 g (41%).
1-[3′-(4″-Methyl-7″-coumaroxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline (3l) was prepared analogously to 3k. Colorless crystals, mp 160-163°C (CH OH), yield 0.8 g (47%).
3
1-[3′-(4″-Nitrophenoxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline(3m).
An oil was precipitated from the filtrate bywater and solidified upon grinding. The solid was filtered off and chromatographed
over Al O with CHCl . The solvent was evaporated. The solid was ground with CCl and filtered off. Colorless compound,
2
3
3
4
mp 140°C (CH CN), yield 1.2 g (78%).
3
1-[3′-(2″,4″-Dichlorophenoxy)propyn-1-yl]-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-
tetrahydroisoquinoline (3n) was prepared analogouslyto3m. The oil from the Al O column was dissolved in acetone, treated
2
3
with conc. HCl (0.5 mL), and cooled with ice. The solid was filtered off, washed with cold acetone, and dried. Colorless
compound, mp 185-190°C, yield 0.75 g (40%).
1-(3′-Phenoxypropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline (3o). The
filtrate was treated with conc. NH OH (10 mL). The oil crystallized upon cooling with ice and grinding. The solid was filtered
4
off and chromatographed over an Al O column with CHCl . The solvent was evaporated. The colorless oil crystallized upon
2
3
3
grinding and was recrystallized from CH OH (5 mL). Colorless crystals, mp 75-80°C, yield 0.83 g (60%).
3
1-(3′-O-Salicylamidopropyn-1-yl)-2-methyl-6,7-methylenedioxy-8-methoxy-1,2,3,4-tetrahydroisoquinoline(3p).
The filtrate was treated with icewater (40 mL). The separated oil crystallized upon grinding. The solid was filtered off, dried,
recrystallized from toluene (40 mL), washed on the filter with petroleum ether, and dried. Colorless crystals, mp 156-158°C,
yield 0.68 g (44%).*
______
*IR spectra of 3 (mineral oil) were not very informative because the triple-bond stretching vibrations did not appear in them.
Therefore, they are not reported.
487

X-ray Structure Analysis of 3d. Crystals of 3d (C H NO ) are monoclinic at room temperature: a = 13.807(6),
15 17
4
3
-1
b = 20.415(8), c = 9.604(5) Å, = 92.23(4)°, V = 2705(2) Å , Z = 8, space group P2 /c, M = 275.30, µ (Mo-K ) = 0.098 mm ,
1
-3
d
= 1.325 g·cm . Intensities of 5109 reflections were measured on an automated four-circle Siemens P3/PC diffractometer
calc
[ (Mo-K ) = 0.71073 Å, graphite monochromator, /2 -scanning, 2 < 50°]. The structure was solved by direct methods and
2
refined by full-matrix anisotropic least-squares methods over F . Hydrogen atoms were placed geometrically at calculated
hkl
positions with the exception of the two hydroxyls (H3 and H3′), which were located in a difference electron-density
synthesis and refined isotropically using the rider method. A total of 4799 independent reflections were used in the refinement
2
(R = 0.1152). The agreement was refined over all independent reflections to wR = 0.2014 calculated over F
[R = 0.0907
1
int
2
hkl
calculated over F for 1175 reflections with I > 2 (I)]. Calculations were performed on an IBM PC AT using the SHELXTL-
hkl
97 program set [16].
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